Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
Nature. 2018 Sep;561(7723):396-400. doi: 10.1038/s41586-018-0467-6. Epub 2018 Aug 29.
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury, but efficient reversal of this regrowth failure remains elusive. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity, (ii) growth-supportive substrate and (iii) chemoattraction-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor delivered via spatially and temporally controlled release from biomaterial depots, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
轴突在成人的解剖完整的脊髓损伤（SCI）中无法再生。多种分子可以在发育过程中或损伤后部分促进或抑制轴突生长，但有效地逆转这种再生失败仍然难以捉摸。在这里，我们表明，在发育过程中对于轴突生长至关重要的三种因素-（i）神经元内在的生长能力，（ii）生长支持性基质和（iii）趋化性-在成人中均被减弱或缺乏-都是单独需要的，并且结合在一起足以刺激成年啮齿动物的解剖完整的 SCI 病变中强有力的轴突再生。我们在 SCI 之前使用骨桥蛋白、胰岛素样生长因子 1 和睫状神经营养因子重新激活成熟的下行 propriospinal 神经元的生长能力；通过成纤维细胞生长因子 2 和表皮生长因子诱导生长支持性基质；并通过生物材料库的时空控制释放来趋化 propriospinal 轴突，该方法放置在 SCI 后顺序进行。我们在小鼠和大鼠中均表明，提供这三种机制的组合而不是单独的机制，可以刺激 propriospinal 轴突通过星形胶质细胞瘢痕边界和跨越非神经组织的病变核心进行强有力的再生，其强度比对照高出 100 倍以上。刺激、支持和趋化的 propriospinal 轴突在病变中心之外再生了整整一个脊髓节段，很好地进入了剩余的神经组织中，形成了具有突触标记的末端样接触，并在病变部位传递了电生理传导能力的显著恢复。因此，克服成熟后解剖完整的 SCI 病变中轴突再生的失败需要联合重新启动几种促进轴突生长的发育必需机制。这些发现为完全性 SCI 病变确定了一种基于机制的生物学修复策略，该策略可以与旨在增强重塑回路功能恢复的康复模型一起使用。
